Preparation of controlled release skeletal muscle relaxant dosage forms

ABSTRACT

The present invention is directed to a method of preparing an extended release pharmaceutical composition comprising cyclobenzaprine, comprising coating inert particles with a cyclobenzaprine-containing a drug layering composition to form IR beads, then coating the IR beads with an extended-release coating to form ER beads.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 61/074,464, filed Jun. 20, 2008, the disclosure of which is hereinincorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

A major objective of developing and commercializing controlled releasedosage forms for indications such as cardiovascular diseases, chronicpain, relief of muscle spasm and associated symptoms especially in theelderly is to deliver the drug so as to maintain the drug attherapeutically effective concentrations over an extended period oftime, thereby enhancing patient compliance and therapeutic efficacy,thereby reducing both cost of treatment and side effects.

Many therapeutic agents are most effective when made available at aconstant rate at or near the absorption site. The absorption oftherapeutic agents thus made available generally results in desiredplasma concentrations leading to maximum efficacy and minimum toxic sideeffects. Much effort has been devoted to developing matrix tablet basedand multi-particulate capsule based drug delivery systems for oralapplications.

U.S. Pat. No. 4,839,177 to Colombo, et al, assigned to Jagotec AG,refers broadly to controlled release of active substances includingmedicaments and any type of substance which is to be released at acontrolled rate into an aqueous fluid. The patent is directed to asystem for the controlled-rate release of active substances consistingof a deposit core comprising an active substance and at least one of (a)a polymeric material having a high degree of swelling on contact withwater and a gellable polymeric material or (b) a single polymericmaterial having both swelling and gelling properties, and a supportplatform applied to the deposit core wherein the support platformconsists of a water insoluble polymeric material.

U.S. Pat. Nos. 4,851,228 and 4,968,507, both to Zentner et al., assignedto Merck & Company, refer to a multi-particulate osmotic pump for thecontrolled release of a pharmaceutically active agent, each osmotic pumpelement consisting essentially of a core containing an active agent anda rate controlling water insoluble wall comprising a semi-permeablepolymer and at least one pH insensitive pore forming additive dispersedthroughout the wall. U.S. Pat. No. 4,590,062 to Jang assigned to TechTrade Corporation and U.S. Pat. No. 4,882,167 to Jang, are directed to acompressed product containing an active produced by dry blending with amatrix combination of a hydrophobic polymer (e.g. ethylcellulose) and awax, fatty acid, neutral lipid or combination thereof.

U.S. Pat. No. 4,996,047 to Kelleher, assigned to Richardson-Vicks, isdirected to an oral pharmaceutical composition in unit dosage form ofion-exchange resin particles having a pharmacologically active drugbound thereto wherein the drug-resin complex particles have been coatedwith a water-impermeable diffusion barrier to provide controlled releaseof the active drug. U.S. Pat. No. 5,120,548 to McClelland et al.,assigned to Merck & Company, is directed to a controlled release drugdelivery device comprising a composition of a polymer which swells uponexposure to an aqueous environment, a plurality of controlled releaseswelling modulators, at least one active agent and either a waterinsoluble polymer coating surrounding the composition or a microporouswall surrounding the composition. U.S. Pat. No. 5,350,584 to McClellandet al., assigned to Merck & Company, relates to a process for theproduction of microcrystalline cellulose-free multiparticulatescomprising a medicament and a charged resin. The resulting spheronizedbeads can be used in certain controlled release dosage forms.

U.S. Pat. No. 5,366,738 to Rork et al., assigned to Merck & Company, isdirected to a drug delivery device for controlled release of an activeagent. The drug delivery device includes a compressed core with anactive agent and a polymer which forms gelatinous microscopic particlesupon hydration and a water insoluble, water impermeable polymericcoating comprising a polymer and plasticizer which surrounds and adheresto the core.

U.S. Pat. No. 5,582,838 to Rork et al., assigned to Merck & Company, isrelated to a drug delivery device for the controlled release of abeneficial agent. The drug delivery device includes a compressed corehaving at least two layers: at least one layer is a mixture of abeneficial agent and a polymer which forms microscopic polymer gel beadsupon hydration and at least one outer layer comprises a polymer whichforms microscopic polymer gel beads upon hydration. A water insoluble,water impermeable coating is applied to the core and the coating hasapertures exposing between about 5-75% of the core surface.

U.S. Pat. No. 5,874,418 to Stella et al., assigned to Cydex, is directedto a pharmaceutical composition comprising a carrier and a mixture of asulfoalkyl ether-cyclodextrin and a therapeutic agent wherein a majorportion of the therapeutic agent is not complexed to the sulfoalkylether-cyclodextrin derivative. Delayed, sustained or controlled releaseformulations are also described wherein the pharmaceutical core iscoated with a film coating comprising a file forming agent and a poreforming agent. U.S. Pat. No. 5,882,682 to Rork et al., assigned to Merck& Company, is directed to a drug delivery process including the steps ofpreparing a uniform mixture of a polymer which forms gelatinousmicroscopic particles upon hydration, the beneficial agent and otherexcipients used in the preparation of the core; compressing the mixtureinto cores; coating the entire core with a water insoluble, waterimpermeable polymeric coating including a polymer and a plasticizer; andforming apertures through the coating.

U.S. Pat. No. 5,952,451 to Zhao, assigned to Guilford Pharmaceuticals isdirected to a process for preparing high molecular weightpoly(phosphoester) compositions comprising a biologically activesubstance and a poly(phosphoester) and the high molecular weightcompositions produced thereby. The polymers so produced are useful inprolonged released drug delivery systems. U.S. Pat. No. 6,004,582 toFaour et al., assigned to Laboratorios Phoenix U.S.A., is directed to amulti-layered osmotic device comprising a compressed core including afirst active agent and an osmotic agent, a semi-permeable membranesurrounding the core and having a preformed passageway therein whereinthe membrane is permeable to a fluid in the environment of use andsubstantially impermeable to the first active agent. The semi-permeablemembrane preferably consists essentially of cellulose acetate andpoly(ethylene glycol). The external coat can includepoly(vinylpyrrolidone) and poly (ethylene glycol) and can furtherincludes materials such as HPMC, ethylcellulose, hydroxylethylcellulose, CMC, dimethylaminoethyl methacrylate-methacrylic acidester copolymer, ethyl acrylate-methyl methacrylate copolymer, andcombinations thereof.

WO 99/18937 to Kleinbart et al., (Merck & Company), is directed to acomposition comprising a pharmaceutically effective amount ofcyclobenzaprine and calcium phosphate dibasic hydrous, wherein thetablet releases most of the active component within an hour. WO 99/30671to Ron E. S., is directed to an oral delivery vehicle including anaspected particle comprising a pharmaceutically active component andexcipients wherein the vehicle is formulated to provide controlleddelivery of the pharmaceutically active component. The vehicle mayfurther contain a coating to provide sustained drug delivery to theparticle. WO 98/53802 to Faour et al., (Laboratorios Phoenix USA), isdirected to a multi-layered osmotic device that is capable of deliveringa first active agent in an outer lamina to one environment of use and asecond active agent in the core to another environment of use. Anerodible polymer coat between an internal semipermeable membrane and asecond active agent-containing external coat comprisespoly(vinylpyrrolidone)-vinyl acetate) copolymer. The active agent in thecore is delivered through a pore containing an erodible plug.

WO 98/18610 to Van Lengerich, is directed to particles containing anactive agent, which provide controlled release of the active ingredientwithout substantial destruction of the matrix material. A release-ratecontrolling component is incorporated in a matrix to control therate-release of the encapsulant from the particles. A hydrophobiccomponent or a high water binding capacity component may be used forextending the release time. Release properties may also be controlled byprecoating the encapsulant and/or coating the particles with afilm-forming component. WO 98/06439 to Oedemoed, (Osteotech), isdirected to a composition comprising a biologically active agentencapsulated in a matrix comprising a polyether ester copolymer, such aspolyethylene glycol terephthalate/polybutylene-terephthalate copolymer.The polyether ester copolymer protects the active agent from degradationand thereby facilitates the drug delivery.

Cyclobenzaprine hydrochloride, a skeletal muscle relaxant, is acentrally acting drug which reduces or abolishes excessive tonic muscleactivity in hypertonic as opposed to hyperphasic disorders. Flexeril® isan immediate release cyclobenzaprine composition in the form of a coatedtablet. Flexeril® tablets are prepared by mixing and compressing thecyclobenzaprine and excipients (lactose, starch, magnesium stearate, andcoloring agents), then coating the resulting tablet with awater-soluble, pharmaceutically acceptable polymer solution(hydroxypropylcellulose/hydroxypropylmethylcellulose). Flexeril® tabletsare available in either 5 mg or 10 mg dosages, and are typicallyadministered three times a day to produce the desired therapeuticeffect. Flexeril® IR (immediate release) tablets containing 10 mg ofcyclobenzaprine HCl are administered three times a day to relieveskeletal muscle spasm of local origin without interfering with musclefunction. The oral administration thrice daily is an issue of patientcompliance, especially with the elderly. Hence, there is a need formodified release skeletal muscle relaxant suitable for a single dailyadministration, particularly in 15 mg and 30 mg dosage forms, tosubstantially minimize intersubject variability and improve the qualityof life, especially in the elderly population.

In addition, it is important to have a manufacturing process thatreproducibly and consistently produces pharmaceutical dosage formsdelivering specified pharmacokinetic properties and performing underreal-world transport and storage conditions. A process that fails toconsistently deliver product meeting approved specifications is notpractical for commercial purposes. Out-of-specification products must bediscarded because they are not guaranteed to deliver the pharmacokineticand stability performance approved by regulatory agencies. Manufacturingprocesses typically involve numerous steps, any one of which couldaffect the pharmacokinetic performance properties of the resultingproduct.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) preparingimmediate release (IR) beads comprising cyclobenzaprine or apharmaceutically acceptable salt, solvate, and/or ester thereof; and b)coating the IR beads with an ER coating composition comprising apharmaceutically acceptable water-insoluble polymer, under an atmospherehaving a dew point ranging from about 5-20° C., thereby forming ERbeads. In another embodiment, the method further comprises coating theIR beads of step a) with a seal-coating composition comprising apharmaceutically acceptable water-soluble polymer before said ER coatingstep b).

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug layered beads;and b) coating the IR beads with an ER coating composition comprising apharmaceutically acceptable water-insoluble polymer, under an atmospherehaving a dew point ranging from about 5-20° C., thereby forming ERbeads. In another embodiment, the method further comprises coating theIR beads of step a) with a seal-coating composition comprising apharmaceutically acceptable water-soluble polymer before said ER coatingstep b).

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug layered beads;b) coating the drug layered beads with a seal-coating compositioncomprising a pharmaceutically acceptable water soluble polymer, therebyforming IR beads; and c) coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug layered beads;b) coating the IR beads with an ER coating composition comprising apharmaceutically acceptable water-insoluble polymer, under an atmospherehaving a dew point ranging from about 5-20° C., thereby forming ERbeads; and c) curing the ER beads at about 60° C. for about 4-12 hoursunder an atmosphere having a dew point ranging from about 5-20° C.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: coating about 20-25mesh inert particles with a drug layering composition comprisingcyclobenzaprine or a pharmaceutically acceptable salt, solvate, and/orester thereof, and a pharmaceutically acceptable solvent, e.g., anaqueous organic solvent; drying the coated inert particles, therebyforming drug layered beads; coating the drug layered beads with a sealcoating composition comprising a pharmaceutically acceptable watersoluble polymer and water; drying the coated drug layered beads, therebyforming IR beads; and coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads. In another embodiment, the present methodis directed to a method of preparing a pharmaceutical compositioncomprising coating about 20-25 mesh inert particles with an about 25 wt.% solids content drug layering composition comprising cyclobenzaprine orpharmaceutically acceptable salts, solvates, and/or esters thereof, andan aqueous organic solvent; drying the coated inert particles, therebyforming drug layered beads; coating the drug layered beads with an about8-10 wt. % solids content seal coating composition comprising apharmaceutically acceptable water soluble polymer and water; drying thecoated drug layered beads, thereby forming IR beads (e.g., drug load:25% w/w); coating the IR beads with an about 6 wt. % solids content ERcoating composition comprising a pharmaceutically acceptablewater-insoluble polymer and an optional plasticizer; drying the coatedIR beads under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads; and optionally curing the sieved ER beadsat about 60° C. for up to about 4 hours, under an atmosphere having adew point ranging from about 5-20° C.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will be described in further detail with reference to theaccompanying Figures wherein:

FIG. 1 shows the proposed target release profile for cyclobenzaprinehydrochloride MR (modified release) capsules.

FIG. 2 shows the simulated Day 1 plasma level following dosing of 1×10mg Flexeril®given 3 times a day and 1×30 mg cyclobenzaprine HCl MRcapsule given once-daily.

FIG. 3 shows a flow diagram of a cyclobenzaprine HCl MR capsuleproduction process.

FIG. 4 shows the plasma concentration—time profiles of CyclobenzaprineHCl modified-release (MR) capsules, 30 mg vs. Fexeril (CyclobenzaprineHCl immediate-release (IR) tablets, 10 mg)×t.i.d. tested in pivotal PKclinical study.

FIG. 5 shows the actual and simulated in-vitro release profiles for CMR30 mg (simulated profile was obtained using the PK parameters derivedfrom the clinical study.

FIG. 6 shows the drug release profiles of Cyclobenzaprine HClmodified-release (MR) capsules, 30 mg stored in induction-sealed HDPEbottles at 40° C./75% RH

DETAILED DESCRIPTION OF THE INVENTION

All documents cited herein are incorporated by reference in theirentirety for all purposes. The citation of any document is not to beconstrued as an admission that it is prior art with respect to thepresent invention.

The terms “drug”, “active”, “active pharmaceutical ingredient”, etc. areused interchangeably.

All references to a particular drug or active herein includepharmaceutically acceptable salts, solvates, esters, isomers, etc.thereof unless expressly indicated otherwise.

In its various embodiments, the present invention is directed to methodsof preparing pharmaceutical compositions as described herein, i.e.,methods for preparing oral dosage forms of skeletal muscle relaxants,for example cyclobenzaprine.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) preparingimmediate release (IR) beads comprising cyclobenzaprine or apharmaceutically acceptable salt, solvate, and/or ester thereof; and b)coating the IR beads with an ER coating composition comprising apharmaceutically acceptable water-insoluble polymer, under an atmospherehaving a dew point ranging from about 5-20° C., thereby forming ERbeads. In another embodiment, the method further comprises coating theIR beads of step a) with a seal-coating composition comprising apharmaceutically acceptable water-soluble polymer before said ER coatingstep b).

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug layered beads;and b) coating the IR beads with an ER coating composition comprising apharmaceutically acceptable water-insoluble polymer, under an atmospherehaving a dew point ranging from about 5-20° C., thereby forming ERbeads. In another embodiment, the method further comprises coating theIR beads of step a) with a seal-coating composition comprising apharmaceutically acceptable water-soluble polymer before said ER coatingstep b).

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug layered beads;b) coating the drug layered beads with a seal-coating compositioncomprising a pharmaceutically acceptable water soluble polymer, therebyforming IR beads; and c) coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads. In one embodiment, the inert particleshave a particle size of about 20-25 mesh. In another embodiment thepharmaceutically acceptable solvent in the drug-layering compositioncomprises an aqueous organic solvent. In another embodiment, theseal-coating composition further comprises water as a solvent.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug layered beads;b) coating the IR beads with an ER coating composition comprising apharmaceutically acceptable water-insoluble polymer, under an atmospherehaving a dew point ranging from about 5-20° C., thereby forming ERbeads; and c) curing the ER beads at about 60° C. for about 4-12 hoursunder an atmosphere having a dew point ranging from about 5-20° C.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug layered beads;b) coating the drug layered beads with a seal-coating compositioncomprising a pharmaceutically acceptable water soluble polymer, therebyforming IR beads; and c) coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads. In yet another embodiment, the presentinvention further comprises curing the ER beads from step c), above atabout 60° C. under an atmosphere having a dew point ranging from about5-20° C. The curing process may be carried out for about 12 hours, about10 hours, about 8 hours, about 6 hours, about 4 hours, or about 2 hours.

In another embodiment, the present invention further comprises a dryingstep after forming the drug-layered beads. For example, the methodcomprises preparing a pharmaceutical composition comprising: (a) coatinginert particles with a drug-layering composition comprisingcyclobenzaprine or a pharmaceutically acceptable salt, solvate, and/orester thereof, and a pharmaceutically acceptable solvent, therebyforming drug-layered beads; (a1) drying the drug-layered beads; (b)coating the drug-layered beads with a seal-coating compositioncomprising a pharmaceutically acceptable water-soluble polymer, therebyforming IR beads; and (c) coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads. In another embodiment, the drying step(a1) is carried out under an atmosphere having a dew point ranging fromabout 5-20° C.

In another embodiment, the present invention further comprises a dryingstep after forming the IR beads. For example, the method comprisespreparing a pharmaceutical composition comprising: (a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug-layered beads;(b) coating the drug-layered beads with a seal-coating compositioncomprising a pharmaceutically acceptable water-soluble polymer, therebyforming IR beads; (b1) drying the IR beads; and (c) coating the IR beadswith an ER coating composition comprising a pharmaceutically acceptablewater-insoluble polymer, under an atmosphere having a dew point rangingfrom about 5-20° C., thereby forming ER beads. In another embodiment,the drying step (b1) is carried out under an atmosphere having a dewpoint ranging from about 5-20° C.

In another embodiment, the present invention further comprises a dryingstep after forming the ER beads. For example, the method comprisespreparing a pharmaceutical composition comprising: (a) coating inertparticles with a drug-layering composition comprising cyclobenzaprine ora pharmaceutically acceptable salt, solvate, and/or ester thereof, and apharmaceutically acceptable solvent, thereby forming drug-layered beads;(b) coating the drug-layered beads with a seal coating compositioncomprising a pharmaceutically acceptable water-soluble polymer, therebyforming IR beads; and (c) coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C.; (c1) drying the coated immediate release beads, thereby forming ERbeads.

In one embodiment, the present invention relates to a method ofpreparing a pharmaceutical composition comprising: (a) coating about20-25 mesh inert particles with a drug layering composition comprisingcyclobenzaprine or a pharmaceutically acceptable salt, solvate, and/orester thereof, and an aqueous organic solvent; b) drying the coatedinert particles, thereby forming drug layered beads; c) coating the druglayered beads with a seal coating composition comprising apharmaceutically acceptable water soluble polymer and water; d) dryingthe coated drug layered beads, thereby forming IR beads; e) coating theIR beads with an ER coating composition comprising a pharmaceuticallyacceptable water-insoluble polymer; f) drying the coated immediaterelease beads under an atmosphere having a dew point ranging from about5-20° C., thereby forming ER beads.

In one embodiment, pharmaceutically acceptable inert particles are firstcoated with a drug layering composition. Non-limiting examples ofsuitable pharmaceutically acceptable particles include sugar spheres orbeads (e.g., Celphere®), cellulose spheres, silicon dioxide spheres,acidic buffer particles, alkaline buffer particles, or the like, havinga suitable particle size or particle size distribution, e.g., about20-25 mesh. In one embodiment, the inert particles are sugar beads(non-pareil seeds) having a particle size of about 20-25 mesh. Inanother embodiment, the drug-containing particles may be prepared bygranulating and milling, by controlled spheroinization in Granurex 40,or by granulation and extrusion/spheroinization to form IR pellets.

The drug layering composition comprises the drug (e.g., cyclobenzaprineand pharmaceutically acceptable salts, solvates, and/or esters thereof)dissolved or dispersed in an aqueous organic solvent. Non-limitingaqueous organic solvents include aqueous ketones or aqueous alcohols,for example aqueous acetone. In one embodiment, the aqueous organicsolvent is 1:1 water/acetone, and the drug is cyclobenzaprinehydrochloride, e.g., dissolved to a solids content of about 25 wt. %.

In other embodiments, the drug layering composition further comprises anoptional binder, for example a pharmaceutically acceptable water solublepolymer such as polyvinylpyrrolidone (PVP), carboxyalkylcelluloses,polyethylene oxide, polysaccharides such as dextran, corn starch,cellulose derivatives such as hydroxypropyl methylcellulose (HPMC) andhydroxypropylcellulose. In one embodiment, the drug layering compositioncontains a binder as described herein. In another embodiment, the druglayering composition does not contain a binder.

The coating weight of the drug layering composition (i.e., the weight ofthe solids dissolved in the aqueous organic solvent deposited on theinert particles, expressed as a percentage weight increase of the beadsafter coating and drying) can vary depending on the desired dosage ofthe drug, and can range from about 5 wt. % to about 30 wt. %, includingabout 5 wt. %, about 10 wt. %, about 15 wt. %, about 20 wt. %, about 25wt. %, or about 30 wt. %. In one embodiment, the coating weight of thedrug layering composition is about 25 wt. %.

The drug layering composition can be applied by any suitable method,including a continuous or batch type fluid bed coating apparatus such asthose manufactured by Glatt. For example, the drug layering can becarried out on a Glatt GPCC 120 equipped with an 18 inch bottom sprayWurster insert (e.g., using a type “C” air distribution plate with 1.5mm holes at the center and 2.0 mm holes that the outer circumference, ora type “D” air distribution plate with 2.0 mm holes at the center and3.5 mm holes at the outer circumference). The fluid bed coatingapparatus can be operated under any suitable conditions which minimizeagglomeration of the drug layered beads during coating, and whichprovide the coating weight described herein. For example, the partitionheight from the distribution plate can be about 53 mm, ranging fromabout 45 mm to about 55 mm. In one embodiment, the partition height fromthe distribution plate is about 53±12 mm. Likewise, the rate at whichthe drug layering composition is sprayed onto the inert particles andthe process air volume (and other operating parameters) can be modified,e.g. to obtain the desired coating weight. For example, in oneembodiment the spray rate ranges from 100 g/min to about 400 g/min, andthe process air volume ranges from about 800-1500 CFM.

In one embodiment, the dried drug layered beads can then be coated witha seal coating composition, for example to improve the mechanicalstrength of the drug layered beads. Any suitable seal coatingcomposition can be used which does not interfere with the properties ofthe extended release coating added in subsequent steps. Suitable sealcoating compositions comprise a pharmaceutically acceptablewater-soluble polymer dissolved or dispersed in water. Non-limitingexamples of water-soluble polymers include polyethylene glycol,hydroxypopylmethylcellulose, hydroxypropylcellulose,hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone andmixtures thereof. In one embodiment, the water-soluble polymer ishydroxypropylmethylcellulose (e.g., Opadry® Clear). The solids contentof the seal coating composition can range from about 2 wt. % to about 10wt. %, for example about 2 wt. %, about 3 wt. %, about 4 wt. %, about 5wt. %, about 6 wt. %, about 7 wt. %, about 8 wt. %, about 9 wt. %, orabout 10 wt. %. In one embodiment, the solids content of the sealcoating composition is about 8-10 wt. %. In another embodiment, thesolids content of the seal coating composition is about 8 wt. %.

In one embodiment, the seal coating step can be carried out, forexample, using a fluid bed coating apparatus as described herein, andcan be dried under suitable conditions, for example in a fluid bedcoating apparatus under temperature conditions as described herein. Forexample, the seal coating composition can be applied to a spray rate ofabout 200 g/min, and dried at a product temperature ranging from about35° C. to about 60° C. In one embodiment, the product temperature isabout 42° C. The resulting seal coated drug layered beads are thenreferred to as “immediate release” (IR) beads because the drug isreleased essentially immediately upon dissolution or administration.

After layering with the drug layering composition, the resulting druglayered beads are dried to remove the aqueous organic solvent. Anysuitable drying conditions can be used which do not degrade the drug(e.g. cyclobenzaprine or its pharmaceutically acceptable salts,solvates, and/or esters). For example, the drug layered beads can bedried in the coating apparatus (e.g., a fluid bed coating apparatus suchas a Glatt fluid bed coater equipped with a Wurster insert). Suitabledrying temperatures are approximately 50° C., for example in the rangeof about 45° C. to about 55° C.

If desired, after drying the IR beads can optionally be “sized” toremove fines (i.e., very fine particles) or agglomerates. For examplethe IR beads can be “sieved” with 14-mesh and 24-mesh screens to removeundersized and oversized particles.

The IR beads are then coated with an “extended release” (ER) coatingcomposition comprising a pharmaceutically acceptable water insolublepolymer. Non-limiting examples of suitable pharmaceutically acceptablewater-insoluble polymers include waxes, water-insoluble cellulosederivatives (e.g. ethylcellulose, ethers of cellulose, esters ofcellulose, cellulose acetate, cellulose butyrates, cellulose propionate,ethyl cellulose mixed cellulose esters, etc), high molecular weighthydroxypropyl methylcellulose with a viscosity of a 2 wt. % aqueoussolution of 3000-5600 cps or higher, acylated polysaccharides,polyurethanes, polyvinyl acetate (e.g., Kollicoat SR30D from BASF),polyacrylate and polymethacrylate polymers and derivatives, neutralcopolymers comprising repeating units of ethyl acrylate and/ormethylmethacrylate (such as Eudragit NE), pH-insensitive ammoniomethacrylic acid copolymers, water-insoluble copolymers of acrylic andmethacrylic acid esters with quaternary ammonium groups, such asEudragit RS, RS30D, RL or RL30D and the like, and combinations thereof.The water-insoluble polymers in the ER coating compositions can beplasticized or unplasticized.

In another embodiment of the present invention, the ER coatingcomposition comprises a water insoluble polymer and a plasticizer.Non-limiting examples of suitable plasticizers include glycerol andesters thereof (e.g., acetylated mono- or diglycerides includingcommercially available Myvacet® 9-45), glyceryl monostearate, glyceryltriacetate, glyceryl tributyrate, dibutyl phthalate, diethyl phthalate,dimethyl phthalate, dioctyl phthalate, acetylcitric acid tributyl ester,acetylcitric acid triethyl ester, tributyl citrate, acetyltributylcitrate, triethyl citrate, glyceroltributyrate; diethyl sebacate,dibutyl sebacate, dibutyl adipates, dibutyl azelates, dibutyl benzoates,chlorobutanol, polyethylene glycols, vegetable oils, diethyl fumarate,diethyl malates, diethyl oxalate, dibutyl succinate, dibutyl butyrate,cetyl alcohol esters, diethyl malonate, castor oils, polysorbates,N-butylbenzenesulfonamide, N-methylpyrrolidone, and mixtures thereof.The plasticizer may comprise about 3 to 30 wt. % (for example about 3wt. %, about 5 wt. %, about 10 wt. %, about 15 wt. %, about 20 wt. %,about 25 wt. %, or about 30 wt. %) and more typically about 10 to 25 wt.% of the ER coating (relative to the amount of water-insoluble polymer).

The ER coating composition can be in the form of a solution (e.g., ofthe water-insoluble polymer and optional plasticizer in a suitablepharmaceutically acceptable solvent), or in the form of a dispersion(e.g., of the water-insoluble polymer and/or optional plasticizer in asuitable pharmaceutically acceptable liquid). In one embodiment, the ERcoating composition comprises an aqueous dispersion of ethylcelluloseand a plasticizer (e.g., dibutyl sebacate). In another embodiment, theER coating composition comprises a solution of ethylcellulose (e.g.,Ethocel Premium Standard 10 cps) and a plasticizer (e.g., diethylphthalate) in acetone/water. In a further embodiment, the ER coatingcomprises a solution of ethylcellulose and diethyl phthalate in 98:2acetone:water. In yet another embodiment, the ER coating contains about90% ethylcellulose and about wt. % diethyl phthalate. In still yetanother embodiment, the ER coating composition comprises a solution ofethylcellulose and diethyl phthalate in a acetone:water mixturecomprising about 85 wt % to 98 wt. % acetone and 15 wt. % to 2 wt. %water including weight ratios of acetone/water of about 88/12, about90/10, about 92/8, and about 95/5 to about 98/2. In still a furtherembodiment, the ER coating composition comprises a solution ofethylcellulose and diethyl phthalate in about 98:2 acetone:water. Inanother embodiment, the ER coating composition comprises a solution ofethylcellulose in about 98:2 acetone.

The solids content of the ER coating composition can vary from about 5wt. % to about 10 wt. %. In one embodiment, the solids content of the ERcoating composition is about 6-7 wt. %. In yet another embodiment, thesolids content of the ER coating composition is about 6.5 wt. %. Instill another embodiment, the ER coating composition comprises asolution of ethylcellulose and diethyl phthalate in acetone/water,having about a 6 wt. % solids content.

The ER coating composition is prepared by stirring a mixture of apharmaceutically acceptable water-insoluble polymer as described herein(e.g. ethylcellulose), optionally a plasticizer as described herein, anda pharmaceutically acceptable solvent (as described herein, e.g. anaqueous organic solvent). In one embodiment, the ER coating compositionis prepared by stirring a mixture of a pharmaceutically acceptablewater-insoluble polymer (e.g. ethylcellulose), a plasticizer (e.g.diethyl phthalate), and a pharmaceutically acceptable solvent (e.g.acetone/water), wherein the resulting solution is stirred after theaddition of the plasticizer for up to 8 hours, but not less than onehour (e.g., for about 1-2 hours, for about 2-6 hours, for about 3-4hours, or about 1 hour) to insure proper homogenization.

The ER composition coating step can be carried out, for example using afluid bed coating apparatus at a spray rate of about 75-700 g/min, usinga process air volume of 700-1500 CFM. The ER coated beads can be driedunder suitable conditions, for example in the fluid bed coatingapparatus under temperature and humidity conditions as described herein,for example at a product temperature of 27-40° C. (typically 33-34° C.at steady state) and dew point of about 5-20° C. (including about 5° C.,about 6° C., about 7° C., about 8° C., about 9° C., about 10° C., about11° C., about 12° C., about 13° C., about 14° C., about 15° C., about16° C., about 17° C., about 18° C., about 19° C., or about 20° C.,inclusive of all values, ranges, and subranges therebetween; typically10° C. at steady state).

If desired, after drying the ER beads can optionally be “sized” toremove fines (i.e., very fine particles) or agglomerates. For examplethe ER beads can be “sieved” with 14-mesh and 24-mesh screens to removeundersized and oversized particles.

Optionally, curing or further drying of the ER beads may be carried out,for example, in a conventional oven, more particularly in a tray-dryingoven. Other drying or curing methods known in the art can also be used(e.g., drying under a gas stream). In one embodiment, the ER beads aredried at a dew point determined to give a desired drug release profile(e.g., after 2 hours, no more than about 40% of the total active isreleased; after 4 hours, from about 40-65% of the total active isreleased; after 8 hours, from about 60-85% of the total active isreleased; and optionally after 12 hours, from about 75-85% of the totalactive is released). In another embodiment, the ER beads are dried at adew point of about 5-20° C. (including about 5° C., about 6° C., about7° C., about 8° C., about 9° C., about 10° C., about 11° C., about 12°C., about 13° C., about 14° C., about 15° C., about 16° C., about 17°C., about 18° C., about 19° C., or about 20° C., inclusive of allvalues, ranges, and subranges therebetween), for example about 6-17° C.or about 8-10° C. Any properly equipped drying apparatus can be used fordrying under dew-point controlled conditions. For example, aconditioning unit that monitors and adjusts dew point can be added tothe drying apparatus. Another suitable method involves using a dryinggas dried using any drying/de-humidifying apparatus, where the dryinggas is dried to the desired dew point.

A lower dew point correlates with drier air. Thus, alternatively, thedrying process may be monitored and adjusted to maintain a desiredrelative humidity. In another embodiment, the ER beads are dried at arelative humidity determined to give a desired drug release profile(e.g., after 2 hours, no more than about 40% of the total active isreleased; after 4 hours, from about 40-65% of the total active isreleased; after 8 hours, from about 60-85% of the total active isreleased; and optionally after 12 hours, from about 75-85% of the totalactive is released). In another embodiment, the ER beads are dried at arelative humidity of about 0-20%, including about 2-10% and about 4-8%at atmospheric pressure.

In addition, drying or curing times and temperatures can be varied, solong as the conditions produce ER beads having a desired drug releaseprofile. In one embodiment, the curing temperature is about 60° C.±5° C.Other curing temperatures such as about 50±5° C. may also be employed.Likewise, curing times may vary, including, for example, up to 24 hours,about 2-24 hours, about 2-12 hours, about 2-6 hours, and about 4 hours.In one embodiment, the ER beads are cured at about 60° C. for about 4hours. In another embodiment, the ER beads are cured while fluidizing atan inlet air temperature of about 60° C. for about 15 min in the fluidbed unit itself.

ER beads prepared as described above have a drug release profile, whentested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm)in 900 mL of 0.1 N HCl (or a suitable dissolution medium) at 37° C.,substantially corresponding to the following pattern:

after 2 hours, no more than about 40% of the total active is released;

after 4 hours, from about 40-65% of the total active is released;

after 8 hours, from about 60-85% of the total active is released; and

optionally after 12 hours, from about 75-85% of the total active isreleased.

When IR beads are coated with the ER coating composition under coatingconditions (e.g., in a fluid bed coating apparatus) in which thetemperature and humidity are maintained to provide a dew point of about5-20° C., and optionally cured at a dew point of about 5-20° C. (e.g.,7-16° C.), the resulting ER beads show improved stability properties.For example, ER beads from commercial capsules, prepared in this mannerand packaged in bottles subjected to long term stability test conditions(e.g., at 25% RH after storage for up to 48 months) consistently providesubstantially uniform dissolution profiles when tested under in vitroconditions. In one embodiment, the ER beads thus prepared providedissolution profiles where the drug concentration does not deviate bynot more than 10% at any time point measured compared to the initialdissolution profile after about 3 months, 6 months, 12 months, 24months, 36 months, or 48 months of storage. Extended release beads thatare prepared using other processing conditions do not consistentlyexhibit comparable stability properties. For example, ER beads that areprepared by coating IR beads with an ER coating composition andoptionally cured under conditions in which the dew point is notcontrolled, or under an atmosphere outside the dew point range of about5-20° C. (e.g., 7-16° C.) do not consistently provide dissolutionprofiles that are stable throughout the expected duration of shelf-life(e.g., after 12 months, 24 months, 36 months, or up to 48 months storagein warehouses or pharmacies).

In addition, the uniformity of the release profile for ER beads in whichthe ER coating comprised a plasticizer was also found to depend on howthe ER coating solution was prepared. In one embodiment, the ER coatingis prepared by dissolving the water insoluble polymer (e.g., ethylcellulose) in a suitable solvent (e.g., an aqueous organic solvent suchas aqueous acetone), then adding the plasticizer to the solution andstirring the solution of water insoluble polymer and plasticizer for atleast one hour after addition of the plasticizer. In some embodiments,the solution of water insoluble polymer and plasticizer is stirred forat least about 2 hours, at least about 3 hours, at least about 4 hours,at least about 5 hours after the addition of the plasticizer. If thewater insoluble polymer and plasticizer solution is stirred for lessthan one hour after the addition of the plasticizer, the resulting ERbeads do not consistently provide dissolution profiles that are stableover time (e.g., under storage conditions).

The cyclobenzaprine compositions prepared by the process of the presentinvention are useful for treating muscle spasms and the pain associatedwith muscle spasms, as well as fibromyalgia (a chronic syndromecharacterized by diffuse or specific muscle, joint, or bone pain,fatigue, and other symptoms) and for the treatment of lower back pain.

The active core of the dosage form of the present invention may becomprised of an inert particle or an acidic or alkaline buffer crystal,which is coated with a drug-containing film-forming formulation andpreferably a water-soluble film forming composition to form awater-soluble/dispersible particle. Alternatively, the active may beprepared by granulating and milling and/or by extrusion andspheronization of a polymer composition containing the drug substance.The amount of drug in the core will depend on the dose that is required,and typically varies from about 5 to 60 weight %. Generally, thepolymeric coating on the active core will be from about 4 to 20% basedon the weight of the coated particle, depending on the type of releaseprofile required and/or the polymers and coating solvents chosen. Thoseskilled in the art will be able to select an appropriate amount of drugfor coating onto or incorporating into the core to achieve the desireddosage. In one embodiment, the inactive core may be a sugar sphere or abuffer crystal or an encapsulated buffer crystal such as calciumcarbonate, sodium bicarbonate, fumaric acid, tartaric acid, etc. whichalters the microenvironment of the drug to facilitate its release.

The drug-containing particle may be coated with an extended release (ER)coating comprising a water insoluble polymer or a combination of a waterinsoluble polymer and a water soluble polymer to provide ER beads. Inaccordance with certain embodiments, the water insoluble polymer and thewater soluble polymer may be present at a weight ratio of from 100/0 to65/35, more particularly from about 95/5 to 70/30, and still moreparticularly at a ratio of from about 85/15 to 75/25. The extendedrelease coating is applied in an amount necessary to provide the desiredrelease profile. The extended release coating typically comprises fromabout 1% to 15%, more particularly from about 7% to 12%, by weight ofthe coated beads.

The present invention also provides a method of making a modifiedrelease dosage form including a mixture of two bead populations. Inaccordance with one embodiment, the method includes the steps of:

-   -   preparing a drug-containing core by coating an inert particle        such as a non-pareil seed, an acidic buffer crystal or an        alkaline buffer crystal with a drug and a polymeric binder or by        granulation and milling or by extrusion/spheronization to form        an immediate release (IR) bead;    -   coating the IR bead with a water-insoluble polymer (optionally        plasticized) alone (such as ethylcellulose) or in combination        with a water soluble polymer (such as        hydroxypropylmethylcellulose) to form an Extended Release (ER)        bead;    -   filling into hard gelatin capsules ER Beads alone or in        combination with IR Beads at a proper ratio to produce MR        (modified release) capsules providing the desired release        profile.

IR beads when tested in accordance with the following procedure releaseat least about 70%, more specifically at least about 90% of the activewithin 30 minutes.

Dissolution Procedure:

Dissolution Apparatus: USP Apparatus 2 (Paddles at 50 rpm), dissolutionmedium: 900 mL 0.1N HCl (or a suitable dissolution medium) at 37° C. andDrug Release determination by HPLC).

An aqueous or a pharmaceutically acceptable solvent medium may be usedfor preparing drug-containing core particles. The type of film formingbinder that is used to bind the drug to the inert sugar sphere is notcritical but usually water soluble, alcohol soluble or acetone/watersoluble binders are used. Binders such as polyvinylpyrrolidone (PVP),polyethylene oxide, hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polysaccharides such as dextran, cornstarch may be used at concentrations from about 0.5 to 5 weight %,although other concentrations may be useful. The drug substance may bepresent in this coating formulation in the solution form or may bedispersed at a solid content up to about 35 weight % depending on theviscosity of the coating formulation.

Examples of appropriate polymers for coating applications include waxes,water-insoluble cellulose derivatives (e.g. ethylcellulose, ethers ofcellulose, esters of cellulose, cellulose acetate, cellulose butyrates,cellulose propionate, ethyl cellulose, mixed cellulose esters, etc),acylated polysaccharides, polyurethanes, polyvinyl acetate (e.g.,Kollicoat SR30D from BASF), polyacrylate and polymethacrylate polymersand derivatives, neutral copolymers comprising repeating units of ethylacrylate and/or methylmethacrylate (such as Eudragit NE), pH-insensitiveammonio methacrylic acid copolymers, water-insoluble copolymers ofacrylic and methacrylic acid esters with quaternary ammonium groups,such as Eudragit RS, RS30D, RL or RL30D and the like, and combinationsthereof. Preferred coating thicknesses range from about 1 to about 1000microns, most preferably between about 20 to about 500 microns.

In accordance with certain embodiments, the drug substance, optionally abinder such as PVP, a dissolution rate controlling polymer (if used),and optionally other pharmaceutically acceptable excipients are blendedtogether in a planetary mixer or a high shear granulator such as Fielderand granulated by adding/spraying a granulating fluid such as water oralcohol. The wet mass can be extruded and spheronized to producespherical particles (beads) using an extruder/marumerizer. In theseembodiments, the drug load could be as high as 90% by weight based onthe total weight of the extruded/spheronized core.

Representative muscle relaxants include cyclobenzaprine, dantrolenesodium, methocarbamol, metaxalone, carisoprodol, diazepam andpharmaceutically acceptable salts, solvates, and/or esters thereof.Cyclobenzaprine hydrochloride is a particularly useful muscle relaxant.As used herein, the useful muscle relaxants include the base,pharmaceutically acceptable salts thereof such as hydrochloride,stereoisomers thereof and mixtures thereof.

Representative examples of water insoluble polymers useful in the ERcoating include waxes, (e.g., fatty acid esters such as glycerylbehenate or caurnuba wax), ethylcellulose powder or an aqueousdispersion (such as AQUACOAT® ECD-30), cellulose acetate, polyvinylacetate (Kollicoat SR#30D from BASF), neutral copolymers based on ethylacrylate and methylmethacrylate (such as Eudragit NE), water-insolublecopolymers of acrylic and methacrylic acid esters with quaternaryammonium groups such as Eudragit RS and RS30D, RL or RL30D and the like.Representative examples of water soluble polymers useful herein includelow molecular weight hydroxypropyl methylcellulose (HPMC),methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone,polyethylene glycol (PEG of molecular weight >3000) and mixturesthereof. The extended release coating will typically be applied at athickness ranging from about 1 weight % up to 15 weight % depending onthe solubility of the active in water and the solvent or latexsuspension based coating formulation used.

The coating compositions used in forming the membranes are optionallyplasticized. Representative examples of plasticizers that may be used toplasticize the membranes include triacetin, tributyl citrate, triethylcitrate, acetyl tri-n-butyl citrate diethyl phthalate, polyethyleneglycol, polypropylene glycol, castor oil, dibutyl sebacate, acetylatedmonoglycerides and the like or mixtures thereof. The plasticizer maycomprise about 3 to 30 wt. % and more typically about 10 to 25 wt. %based on the polymer. The type of plasticizer and its content depends onthe polymer or polymers, nature of the coating system (e.g., aqueous orsolvent based, solution or dispersion based and the total solids).

In general, it is desirable to prime the surface of the particle beforeapplying an extended release membrane coating or to separate thedifferent membrane layers by applying a thin hydroxypropylmethylcellulose (HPMC) (OPADRY® Clear) film. While HPMC is typicallyused, other primers such as hydroxypropylcellulose (HPC) can also beused.

The membrane coatings can be applied to the core using any of thecoating techniques commonly used in the pharmaceutical industry, butfluid bed coating is particularly useful.

The present invention is applied to multi-dose forms, i.e., drugproducts in the form of multi-particulate dosage forms (pellets, beads,granules or mini-tablets) or in other forms suitable for oraladministration. As used herein, these terms are used interchangeably torefer to multi-particulate dosage forms.

The invention also provides a method of making an extended releasedosage form which includes a mixture of two or more bead populations. Inaccordance with one aspect of the present invention, the method includesthe steps of:

coating an inert particle such as a non-pareil seed, an acidic buffercrystal or an alkaline buffer crystal with a drug and polymeric binderto form an active drug particle (IR beads), which may be present in theunit dosage form to act as a bolus dose;

coating the active drug particle with a solution or suspension of awater insoluble polymer or a mixture of water soluble and waterinsoluble polymers to form an extended release coated drug particle (ERbeads);

filling into a hard gelatin capsule ER beads alone and optionally, incombination with IR beads at a proper ratio ranging from 95/5 to 70/30(ER beads/IR beads) to produce a MR (modified release) capsuleexhibiting a target drug release profile.

The methods of the present invention provide a modified release,multi-particulate dosage form of a skeletal muscle relaxant comprisingone or more bead populations which provides an extended release profileof the active under in vitro conditions closely mimicking the profilesimulated from pharmaco-kinetic modeling. At least one of the beadpopulations is an ER (extended release) bead population typicallycomprising a coating of a water insoluble polymer alone, or incombination with a water soluble polymer, applied onto active containingcores. The active core of the dosage form of the present invention maycomprise an inert particle such as a sugar sphere, or an acidic oralkaline buffer crystal, which is coated with a skeletal muscle relaxantsuch as cyclobenzaprine hydrochloride-containing film-formingformulation, preferably a water-soluble film forming composition. Thefirst coating formulation may contain, in addition to the active, abinder such as hydroxypropyl cellulose. The drug layered beads may becoated with a protective seal coating of OPADRY® Clear to produce IRBeads. Alternatively, the core particle may be formed by granulating anddry milling and/or by extrusion and spheronization of a pharmaceuticalcomposition containing the active. The amount of drug in the core willdepend on the dose required and typically varies from about 5 to about60% by weight.

ER Beads prepared by the methods of the present invention comprise afunctional membrane (e.g., extended release membrane) comprising a waterinsoluble polymer alone or in combination with a water soluble polymeronto IR Beads. The capsule formulation for once a day, oraladministration of a skeletal muscle relaxant prepared in accordance withthe present invention comprises ER Beads containing the active substanceand optionally IR Beads. IR (immediate release) Beads allow immediaterelease of the active while ER Beads allow an extended release profileof the active over several hours. Upon oral administration, such acapsule formulation provides for therapeutically effective plasmaprofiles over an extended period of time, thereby resulting in improvedpatient compliance.

The dosage forms prepared by the methods of the present inventioninclude one or more bead populations and provide a modified releaseprofile. At least one of the bead populations includes extended release(ER) beads wherein the ER beads include a core particle (IR (immediaterelease) bead) containing a skeletal muscle relaxant and an ER (extendedrelease) coating comprising a water insoluble polymer surrounding thecore. The dosage form, in accordance with certain embodiments, whendissolution tested using United States Pharmacopoeia Apparatus 2(paddles @ 50 rpm) in 900 mL of 0.1N HCl (or a suitable dissolutionmedium) at 37° C. exhibits a drug release profile substantiallycorresponding to the following pattern:

after 2 hours, no more than about 40% of the total active is released;

after 4 hours, from about 40-65% of the total active is released;

after 8 hours, from about 60-85% of the total active is released; and

optionally after 12 hours, from about 75-85% of the total active isreleased.

The dosage form thereby provides a therapeutically effective plasmaconcentration over an extended period of time, typically over a periodof 24 hours to treat muscle spasm associated with painfulmusculoskeletal conditions in humans. Alternatively, the dosage formsprepared by the methods of the present invention may be used to treatfibromyalgia or insomnia.

The following non-limiting examples illustrate the capsule dosage formsmanufactured in accordance with the invention using cyclobenzaprinehydrochloride as a test case, which exhibit in vitro drug releaseprofiles, similar to that predicted by performing modeling exercises.Such dosage forms when orally administered, would enable maintainingdrug plasma concentrations at therapeutically effective levels overextended periods of time, thereby significantly improving patientcompliance.

Example 1

Cyclobenzaprine is well absorbed after oral administration, but there isa large intersubject variation in plasma levels. It is eliminated quiteslowly with a half-life as long as one to three days. The presenttreatment regimen of 10 mg three times daily is an issue of patientcompliance, especially the elderly. Hence, a modified release dosageform (capsule) was designed with a release profile shown in FIG. 1. Todetermine if this is the proper release profile, the pharmacokineticsdata of cyclobenzaprine following a single dose of 10 mg Flexeril®tablets administered 3 times a day was taken from the literature. Apharmacokinetic model was developed from this data using WinNonlin™Version 1.5.

The resulting model parameters are listed below:

Model Parameter Value Volume of Distribution/F 429 L K01 0.2031 hr⁻¹ K100.1004 hr⁻¹ K12 0.0828 hr⁻¹ K21 0.0398 hr⁻¹ Tlag 0 hr Dose 2 × 10 mgTablets

Theoretical plasma levels were simulated using the pharmacokinetic modelgiven above and the target in vitro release rate given in FIG. 1. FIG. 2shows the simulated plasma levels for day one following dosing of 1×10mg Flexeril® tablet given 3 times a day and the proposed CyclobenzaprineHCl MR Capsule, 30 mg given once a day.

Example 2A

A manufacturing process flow diagram is shown in FIG. 3, used to preparecyclobenzaprine HCl MR capsules. (See U.S. Pat. No. 7,387,793, hereinincorporated by reference in its entirety for all purposes.) Thecapsules used for the various clinical studies (e.g., pivotal study andphased clinical trials) and the registration stability batches were alsoprepared according to the process of Example 2A.

A drug solution (25 wt. % solids) comprising cyclobenzaprinehydrochloride (20.0 kg) prepared in 50/50 acetone/purified water (30.0kg each) and coated onto 20-25 mesh sugar spheres (58.4 kg) in a Glattfluid bed coater, GPCG 120, equipped with a 18″ bottom spray Wursterinsert, air distribution plate D (100 mesh screen), a partition heightfrom the distribution plate of about 53 mm, at the following conditions:Nozzle diameter: 3.0 mm; dew point about 8° C.; Atomization airpressure: 2 bar; Initial spray rate: 100 g/min ramping up to about 400g/min; Product temperature: 49° C., decreasing to 43° C.; Process airvolume: 950-1100 CFM. The resulting drug layered beads were providedwith a protective seal coat of OPADRY® Clear at a coating level of 2 wt.% in the Glatt fluid bed coater by spraying the aqueous solution (8 wt.% solids) at a spray rate of about 200 g/min at a product temperature of42° C. at a dew point of 8° C., then dried at about 50° C. for 5 minutesat a dew point of 8° C. to provide “immediate release” (IR) beads.

An ER coating composition (6.0 wt. % solids) comprising ethylcellulose(6.9 kg, Ethocel Premium Std, 10 cps) and diethyl phthalate (0.75 kg) ina 98/2 acetone/water solution was prepared by mixing at 850±25 rpm fornot less than one hour. This means the time of mixing could be avariable at the discretion of the operator in the manufacturingenvironment. This coating composition was then applied onto the IR Beads(77.4 kg) under a dew point of 10° C. at an initial spray rate of about250 g/min, ramping up to 500 g/min, process air volume of 1000 CFM),process air temperature 46° C., atomization air pressure 2.5 bar, in aGlatt GPCG 120, equipped with a 18″ bottom spray Wurster insert, airdistribution plate C (100 mesh screen), a partition height from thedistribution plate of about 50 mm, nozzle port size 3 mm. The ER coatingwas applied at a dew point of 10° C. to provide a 9% coating weight. Theresulting ER beads were dried in the unit at 50° C. for about 5 min at adew point of 10° C. to drive-off residual solvents.

The ER beads were then passed through 14-mesh and 24-mesh screens,discarding any beads remaining on the 14 mesh screen, then cured in anoven at 60° C. for 4 hours. The required amounts of extended releasebeads (131.9 mg equivalent to 30 mg of cyclobenzaprine HCl) were thenfilled into size 4 capsules (empty capsule weight: 37 mg) to produceCyclobenzaprine HCl MR Capsules, 30 mg as pivotal clinical trialmaterial (CTM) using production-scale capsule filling equipment, MGFutura. The required amounts of extended release beads (65.9 mgequivalent to 15 mg of cyclobenzaprine HCl) and equivalent amounts of20-25 mesh sugar spheres were also filled into size 4 white opaquecapsules to produce Cyclobenzaprine HCl MR Capsules, 15 mg as pivotalCTM using the same capsule filler. Size 4 hard gelatin capsules with abody and cap colored differently and an identifying logo were employedfor producing commercial products as Cyclobenzaprine HCl MR capsules, 15& 30 mg.

Example 2B

A modified process was developed according to Example 2A withmodifications to the ER coating and oven-curing steps. In the modifiedprocess, the IR beads were prepared as in Example 2A. In the ER coatingstep, the ER coating composition (prepared as in Example 2A) comprisingethylcellulose and diethyl phthalate in the acetone/water solution wasprepared by mixing at 850±25 rpm for not less than 1 hr after theaddition of diethyl phthalate. This coating composition was then appliedonto the IR Beads at a dew point of 10° C. to provide a 9% coatingweight. The resulting ER beads were dried in the unit at 50° C. forabout 5 min at a dew point of 10° C. to drive-off residual solvents.After screening (14- and 24-mesh screens), the ER beads were cured in anoven at 60° C. for 4 hours at a dew point of 8-10° C. (target 10° C.).

Example 3

Compositions prepared according to the procedure of Example 2A weretested in pharmacokinetic (PK) and Phase 3 clinical studies (fasted vs.fed state study using CMR mg doses), safety and bioavailability study ofmultiple dosing of Cyclobenzaprine HCl MR 30 mg and Cyclobenzaprine HCl10 mg three times daily in healthy volunteers, efficacy and safety studyof Cyclobenzaprine HCl MR 15 mg and 30 mg vs. Placebo in subjects withpain due to muscle spasms of local origin, and a randomized,double-blind, two-period crossover trial in healthy volunteers (each7-day assessment period). The latter trial compared the safety andpharmacokinetics of Cyclobenzaprine HCl Modified-Release (CMR) 30 mgonce daily and Flexeril (cyclobenzaprine HCl 10 mg three times daily intwo sub-groups of 18 healthy volunteers—aged 18 to 45 years and aged 65to 75 years. Each 7-day assessment period consisted of blood collectionand safety assessments at Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8,10, 12, 14, 16, 18, 20, 22, 24, 36, 48, 72, 96, 120, 144, and 168 hrsafter dosing and bioanalytical testing by validated LC-MS/MS. FIG. 4shows the plasma concentration—time profiles of cyclobenzaprine HCl MR(CMR 30 mg) and Flexeril® (10 mg×3 times) administered into healthyadult volunteers fasted overnight.

TABLE 1A Summary of target pharmacokinetic (PK) parameters in healthyadult subjects. Parameter Mean ± SD CMR 15 mg CMR 30 mg AUC₀₋₁₆₈ (ng ·hr/mL) 318.3 ± 114.7 736.6 ± 259.4 AUC_(0-∞) (ng · hr/mL) 354.1 ± 119.8779.9 ± 277.6 C_(max) (mg/mL) 8.3 ± 2.2 19.9 ± 5.9  T_(max) (hrs) 8.1 ±2.9 7.1 ± 1.6 T_(1/2) (hrs) 33.4 ± 10.3 32.0 ± 10.1

Accordingly, one aspect of the invention relates to a process forpreparing cyclobenzaprine HCl dosage forms for providing thepharmacokinetic (PK) parameters listed in Table 1A, obtained in theclinical studies described above, and, in another aspect, bioequivalentdosage forms, providing 80% to 125% of one or more of the meanpharmacokinetic parameters listed in Table 1A (e.g., C_(max) and AUC).Each of the MR dosage forms containing cyclobenzaprine hydrochloride tobe manufactured for commercial distribution following the regulatoryapproval, if tested in healthy volunteers, should provide a maximumblood plasma concentration (C_(max)) within the range of about 80% to125% of 19.851±5.8765 ng/mL of cyclobenzaprine HCl and an AUC₀₋₁₆₈within the range of about 80% to 125% of 736.60±259.414 ng·hr/mLfollowing oral administration of a single 30 mg cyclobenzaprine HCl MRCapsule. Similarly, the cyclobenzaprine MR dosage forms should provide amaximum blood plasma concentration (C_(max)) within the range of about80% to 125% of 8.315±2.1635 ng/mL of cyclobenzaprine HCl and an AUC₀₋₁₆₈within the range of about 80% to 125% of 318.30±114.657 ng·hr/mLfollowing oral administration of a single 15 mg cyclobenzaprine HCl MRCapsule.

Cyclobenzaprine HCl MR capsules of 30 mg were prepared according toExample 2A, providing within 80% to 125% of the mean pharmacokineticvalues shown in Table 1B in healthy adult subjects aged 18-45 yearsunder fasting conditions, and in Table 1C in healthy adult subjects aged65-75 years under fasting conditions. AUC₀₋₁₆₈ refers to the area underthe plasma concentration-time curve to the last measurable time point(168 hrs) calculated by the linear trapezoidal rule, AUC_(0-∞) refers toarea under the concentration-time curve to infinity, C_(max) refers tothe maximum blood plasma concentration and T_(max) refers to the time tomaximum plasma levels of cyclobenzaprine. C_(max(first)) andT_(max(first)) values were estimated using plasma levels after the firstdose and before second dose for cyclobenzaprine 10 mg TID, whereas forCMR 30 mg, the entire study period was used and the value wasdose-adjusted to a 10-mg dose. T_(max) was estimated using plasma levelsduring the entire study period for both study medications.

TABLE 1B Mean (±SD) PK parameters for subjects 18 to 45 years of age inthe Safety population Flexeril ® 10 mg; CMR 30 mg Parameter tid (n = 17)(n = 18) AUC₀₋₁₆₈ (ng · hr/mL) 805.4 ± 330.7 715.1 ± 264.2 AUC_(0-∞) (ng· hr/mL) 837.4 ± 340.2 751.2 ± 271.5 C_(max (first)) (ng/mL)^(a) 13.0 ±4.6  6.4 ± 1.9 C_(max) (ng/mL)^(b) 18.1 ± 5.4  19.2 ± 5.6 T_(max (first)) (hrs)^(a) 4.3 ± 1.0 6.8 ± 1.9 T_(max) (hrs)^(b) 17.2 ±5.7  6.8 ± 1.9 t_(1/2) (hrs) 30.4 ± 7.1  32.4 ± 8.1  ^(a)Estimated usingplasma levels after the first dose and before second dose forcyclobenzaprine 10 mg TID; for CMR 30 mg, the entire study period wasused and the value was dose-adjusted to a 10-mg dose. ^(b)Estimatedusing plasma levels during the entire study period for both studymedications.

TABLE 1C Mean (±SD) PK parameters for subjects 65 to 75 years of age inthe Safety population Flexeril ® 10 mg; CMR 30 mg Parameter tid (n = 17)(n = 18) AUC₀₋₁₆₈ (ng · hr/mL) 1017.4 ± 261.3 945.9 ± 255.2 AUC_(0-∞)(ng · hr/mL) 1129.1 ± 309.6 1055.2 ± 301.9  C_(max (first)) (ng/mL) 12.2± 2.6 6.4 ± 1.7 C_(max) (ng/mL) 18.5 ± 3.3 19.2 ± 5.1  T_(max (first))(hrs)  5.0 ± 1.4 8.5 ± 2.3 T_(max) (hrs) 19.7 ± 5.0 8.5 ± 2.3 t_(1/2)(hrs) 47.1 ± 9.4 49.0 ± 8.3 

FIG. 5 shows the actual in vitro drug release profile in comparison tothe simulated in vitro drug release profile calculated using theGastro-Plus software and the PK parameters obtained from the studiesdescribed above. The two profiles are remarkably very close. FIG. 6shows the drug release profiles of the pivotal biobatch (30 mg, preparedaccording to Example 2A) stored in 60-ct induction-sealed HDPE bottlesunder accelerated stability conditions (40 C/75% RH (relativehumidity)). 15 mg (PF307EA001) and all Registration stability batches(PF312 (15 mg) and PF313 (30 mg), also prepared according to Example 2A)exhibited similarly tight drug release profiles when stored in 60-ctinduction-sealed HDPE bottles under ICH stability conditions (e.g., at25° C./60% RH for 36 months, 30° C./65% RH for 12 months, and 40° C./75%RH for 6 months).

Example 4

Table 2 summarizes the stability results for a series of processvalidation batches of Cylcobenzaprine HCl MR capsules, 15 and 30 mg(e.g., PF312EA001V to PF312EA003V (15 mg) and PF313EA001V toPF313EA003V, prepared according to Example 2A). The first validationbatch (PF313EA001) and another batch (PF313EA006) had comparatively highand low dissolutions at release (i.e., at time zero), respectively (seeTable 3). Lot#PF3130001V failed for dissolution at 1-, 3-, and 6-month40° C./75% RH (relative humidity), 3-, 6-month 25° C./60% RH and 3 monthat 30° C./65% RH time points. The out-of-specification dissolutionpoints were the 4 hour and/or 8 hour time points. The other fivevalidation batches at release (i.e., at time zero) met dissolution,assay, degradant specifications (see Table 2). Furthermore, thestability data for these validation batches also met the productspecifications. The investigation indicated the out-of-specification(OOS) dissolution results observed for PF3130001V were not due to astability issue with the product but rather a higher than typicaldissolution profile for this particular lot at release (i.e., at timezero). The time zero and subsequent time dissolution data did notindicate an upward trend in the dissolution values but rather typicalanalytical and/or batch-to-batch variability.

TABLE 2 Analytical Data for Cyclobenzaprine HCl MR Capsules, 15 & 30 mg(Process Validation Batches) Cyclobenzaprine HCl Assay Moisture % DrugReleased Total % MR Capsule (%) (%) 2 hrs 4 hrs 8 hrs 16 hrs ImpurityCyclobenzaprine HCl MR Capsules, 30 mg Validation Batch PF3130001V inHDPE Bottle Initial 100.1 2.1 36 (34-38) 60 (57-62) 80 (76-83) 93(88-96) 0.0 25° C./60% RH, 3 mo 100.3 1.6 36 (34-37) 62 (60-65) 82(79-86) 97 (95-101) 0.2 25° C./60% RH, 6 mo 99.9 2.1 37 (36-39) 63(58-67) 84 (77-88) 99 (94-103) 0.1 25° C./60% RH, 12 mo 101.2 2.7 33(31-34) 58 (56-59) 76 (74-78) 89 (87-92) 0.2 40° C./75% RH, 1 mo 100.02.3 36 (35-38) 61 (59-64) 82 (78-87) 93 (90-97) 0.1 40° C./75% RH, 3 mo99.0 2.2 35 (33-38) 62 (59-65) 83 (79-85) 97 (94-101) 0.2 40° C./75% RH,6 mo 100.3 2.0 34 (33-36) 63 (60-65) 84 (80-87) 98 (95-99) 0.2Cyclobenzaprine HCl MR Capsules, 30 mg Validation Batch PF3130002V inHDPE Bottle Initial 99.7 1.9 31 (30-33) 56 (54-58) 75 (73-78) 88 (86-92)0.0 25° C./60% RH, 3 mo 98.9 2.0 32 (30-33) 59 (56-61) 80 (76-83) 97(93-100) 0.1 25° C./60% RH, 6 mo 98.7 1.5 30 (28-32) 56 (54-59) 77(74-80) 93 (89-95) 0.2 25° C./60% RH, 12 mo 101.5 1.8 31 (28-32) 56(54-57) 74 (71-75) 88 (85-89) 0.0 25° C./60% RH, 18 mo 101.2 2.0 29(27-30) 54 (51-56) 73 (69-76) 87 (82-92) 0.1 40° C./75% RH, 1 mo 100.32.4 31 (30-31) 58 (56-59) 78 (76-79) 93 (90-96) 0.2 40° C./75% RH, 3 mo98.3 2.1 31 (30-32) 58 (57-59) 79 (78-80) 94 (93-97) 0.1 40° C./75% RH,6 mo 100.8 1.5 29 (28-29) 56 (55-57) 76 (74-79) 91 (89-93) 0.3Cyclobenzaprine HCl MR Capsules, 30 mg Validation Batch PF3130003V inHDPE Bottle Initial 98.0 2.3 31 (30-32) 56 (54-58) 76 (73-78) 90 (88-93)0.0 25° C./60% RH, 3 mo 98.0 2.0 32 (30-34) 58 (56-60) 78 (76-80) 91(89-93) 0.1 25° C./60% RH, 6 mo 97.9 1.9 33 (30-34) 57 (52-62) 77(72-82) 94 (90-97) 0.2 25° C./60% RH, 12 mo 98.7 2.3 30 (29-30) 55(53-56) 74 (73-75) 88 (86-90) 0.3 25° C./60% RH, 18 mo 98.7 1.9 29(27-31) 54 (52-56) 73 (69-75) 87 (82-90) 0.1 40° C./75% RH, 1 mo 98.52.0 32 (30-34) 57 (54-60) 77 (73-80) 90 (86-94) 0.3 40° C./75% RH, 3 mo96.6 2.2 30 (28-31) 57 (54-59) 78 (74-81) 92 (87-95) 0.1 40° C./75% RH,6 mo 98.9 1.3 29 (27-30) 57 (54-59) 80 (74-83) 93 (88-96) 0.2Cyclobenzaprine HCl MR Capsules, 15 mg Validation Batch PF3120001V inHDPE Bottles Initial 98.4 2.6 24 (22-26) 50 (48-51) 71 (65-74) 87(78-91) 0.0 25° C./60% RH, 3 mo 96.2 1.9 26 (21-29) 53 (48-56) 74(69-79) 90 (86-94) 0.1 25° C./60% RH, 6 mo 96.5 1.7 28 (22-31) 55(50-58) 77 (73-79) 92 (89-95) 0.2 25° C./60% RH, 12 mo 97.2 2.4 23(22-26) 50 (48-52) 71 (67-74) 87 (80-91) 0.2 25° C./60% RH, 18 mo 96.02.0 22 (20-25) 49 (46-52) 71 (67-73) 85 (81-88) 0.1 40° C./75% RH, 1 mo97.3 2.5 24 (23-28) 51 (49-54) 72 (69-74) 88 (84-90) 0.1 40° C./75% RH,3 mo 95.6 2.3 24 (20-27) 53 (47-60) 75 (70-80) 91 (86-93) 0.1 40° C./75%RH, 6 mo 98.3 1.9 22 (17-29) 51 (49-56) 74 (71-79) 90 (86-96) 0.2Cyclobenzaprine HCl MR Capsules, 15 mg Validation Batch PF3120002V inHDPE Bottles Initial 99.6 2.4 23 (21-27) 50 (47-54) 72 (69-75) 88(86-91) 0.0 25° C./60% RH, 3 mo 100.7 2.1 24 (22-26) 53 (49-54) 75(70-76) 91 (85-92) 0.1 25° C./60% RH, 6 mo 98.4 1.8 26 (22-29) 55(46-59) 75 (69-82) 94 (91-97) 0.1 25° C./60% RH, 12 mo 99.8 2.1 24(22-25) 52 (49-55) 73 (70-76) 87 (84-92) 0.2 25° C./60% RH, 18 mo 99.22.0 22 (17-28) 51 (45-56) 73 (69-78) 93 (88-99) 0.1 40° C./75% RH, 1 mo99.2 2.4 22 (19-24) 50 (47-54) 72 (69-76) 89 (85-94) 0.1 40° C./75% RH,3 mo 98.9 2.3 27 (25-28) 54 (52-56) 76 (72-80) 92 (87-97) 0.1 40° C./75%RH, 6 mo 99.9 2.0 23 (20-25) 54 (52-58) 75 (71-81) 88 (84-90) 0.1Cyclobenzaprine HCl MR Capsules, 15 mg Validation Batch PF3120003V inPVC Blisters Initial 96.3 2.1 24 (21-27) 52 (50-53) 73 (71-75) 88(85-91) 0.0 25° C./60% RH, 3 mo 98.6 2.2 22 (19-25) 49 (47-51) 71(68-73) 87 (83-89) 0.0 25° C./60% RH, 6 mo 98.2 1.9 20 (17-23) 48(45-51) 70 (68-71) 85 (83-88) 0.0 25° C./60% RH, 12 mo 97.8 2.9 24(21-25) 49 (46-50) 68 (65-71) 83 (78-87) 0.1 25° C./60% RH, 18 mo 98.22.3 20 (17-22) 47 (43-51) 68 (64-72) 83 (80-87) 0.0 40° C./75% RH, 1 mo99.7 3.0 24 (22-26) 53 (50-57) 76 (74-81) 92 (89-99) 0.1 40° C./75% RH,3 mo 98.6 2.3 24 (22-25) 51 (47-53) 74 (71-76) 90 (87-92) 0.1 40° C./75%RH, 6 mo 99.2 2.5 24 (23-24) 50 (48-52) 72 (69-76) 88 (83-92) 0.0

Two modifications were made to the process of Example 2A. First, thestirring time after addition of plasticizer in the ER coating solutionwas consistently controlled to be at least one hour with an upper limitof, for example, 2 hrs. Second, a desiccant wheel was installed totightly control the dew point during drying/curing. A target dew pointfor drug layering, ER bead coating, and ER bead curing was set at 8-10°C.

Table 3 summarizes the mean values with standard deviations, maximum andminimum values of assay, dissolutions, moisture, total degradants, anduniformity of dosage units for the commercial batches after the newcontrols were consistently adopted (i.e., stirring time and curing dewpoint control of Example 2B): 7 batches of cyclobenzaprine HCl MRcapsules, 30 mg (PF313) and 32 batches of cyclobenzaprine HCl MRcapsules, 15 mg (PF312). The earlier Process Validation Batch PF3130001Vand one of the first 3 commercial batches (PF3130006) referred to above(manufactured according to Example 2A) which showed atypical (i.e., highor low) dissolution values, are shown separately in Table 3. It isapparent that the assay and dissolution values are tight, indicatingthat the manufacturing processes are sufficiently robust.

TABLE 3 Analytical Data for 15 & 30 mg Cyclobenzaprine HCl MR CapsulesAssay Total Uniformity of Dosage Units Cyclobenzaprine HCl Mean Moisture% Drug Released Impurity Assay Mean MR Capsules (%) (%) 2 hrs 4 hrs 8hrs 16 hrs (%) (%) Stdev Validation Batch (PF3130001V) and CommercialBatch (PF3130006) of Cyclobenzaprine HCl MR Capsules, 30 mg, withAtypical Drug Release Profiles PF313EA001V 101.3 1.7 35 60 79 93 0.03100.0 4.1 PF313EA006 100.7 1.0 20 46 67 84 0.00 101.1 5.8 Mean of 7Batches of Cyclobenzaprine HCl MR Capsules 30 mg (PF313) Mean 100.4 1.5430.3 55.7 75.2 89.3 0.07 100.9 2.55 Stdev 0.96 0.18 3.0 3.5 3.8 3.5 0.041.49 0.56 Max (%) 101.9 1.9 35 61 80 93 0.11 103.7 3.25 Min (%) 99.3 1.426 51 69 84 0.02 99.4 1.69 Mean of 32 Batches of Cyclobenzaprine HCl MRCapsules 15 mg (PF312) Mean 99.6 2.1 24.1 50.5 71.2 86.7 0.066 99.8 3.38Stdev 2.72 0.52 3.40 3.64 3.76 3.54 0.049 2.88 1.03 Max (%) 103.9 3.0 3358 79 93 0.20 106.3 5.81 Min (%) 92.2 1.0 17 43 63 79 0.00 94.7 1.74

While the invention has been described in detail and with reference tospecific examples thereof, it will be apparent to one skilled in the artthat various changes and modifications can be made without departingfrom the spirit and scope thereof.

1. A method of preparing a pharmaceutical composition comprising: a)coating inert particles with a drug layering composition comprisingcyclobenzaprine or a pharmaceutically acceptable salt, solvate, and/orester thereof, and a pharmaceutically acceptable solvent, therebyforming IR beads; and b) coating the IR beads with an ER coatingcomposition comprising a pharmaceutically acceptable water-insolublepolymer, under an atmosphere having a dew point ranging from about 5-20°C., thereby forming ER beads.
 2. The method of claim 1, furthercomprising: c) curing the ER beads at about 60° C. for about 4-12 hoursunder an atmosphere having a dew point ranging from about 5-20° C. 3.The method of claim 1, further comprising coating the IR beads of stepa) with a seal-coating composition comprising a pharmaceuticallyacceptable water-soluble polymer before said ER coating step b).
 4. Themethod of claim 3, wherein said inert particles have a particle size ofabout 20-25 mesh.
 5. The method of claim 1, wherein said seal-coatingcomposition further comprises water.
 6. The method of claim 1, whereinsaid coating steps a) and b) are carried out under an atmosphere havinga dew point ranging from about 5-20° C.
 7. The method of claim 1,wherein the ER coating composition further comprises a plasticizer. 8.The method of claim 7, wherein the ER coating composition is prepared bystirring the pharmaceutically acceptable water-insoluble polymer,plasticizer, and pharmaceutically acceptable solvent for at least about1 hour after addition of the plasticizer to the pharmaceuticallyacceptable water-insoluble polymer and pharmaceutically acceptablesolvent.
 9. The method of claim 8, wherein the pharmaceuticallyacceptable water-insoluble polymer, plasticizer, and pharmaceuticallyacceptable solvent are stirred for at least about 3 hours after additionof the plasticizer to the pharmaceutically acceptable water-insolublepolymer and pharmaceutically acceptable solvent.
 10. The method of claim1, wherein the drug layering composition further comprisescyclobenzaprine hydrochloride and about 50:50 acetone:water.
 11. Themethod of claim 1, wherein the pharmaceutically acceptable water-solublepolymer comprises hydroxypropyl methylcellulose.
 12. The method of claim1, wherein the pharmaceutically acceptable water-insoluble polymer isselected from the group consisting of ethylcellulose, ethers ofcellulose, esters of cellulose, cellulose acetate, cellulose butyrate,cellulose propionate, polyvinyl acetate, neutral copolymers based onethyl acrylate and methyl methacrylate, copolymers of acrylic andmethacrylic acid esters with quaternary ammonium groups, pH-insensitiveammonio methacrylic acid copolymers, waxes, acetylated polysaccharides,polyurethanes, high molecular weight hydroxypropyl methylcellulose,polyacrylate and polymethacrylate polymers, and mixtures thereof. 13.The method of claim 1, wherein the pharmaceutically acceptablewater-insoluble polymer comprises ethylcellulose.
 14. The method ofclaim 7, wherein the plasticizer is selected from the group consistingof diethyl phthalate, triacetin, tributyl citrate, tri-ethyl citrate,acetyl tri-n-butyl citrate, dibutyl sebacate, polyethylene glycol,polypropylene glycol, castor oil, acetylated mono- and di-glycerides,glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate,phthalates, citrates, glyceroltributyrate; sebacates, adipates,azelates, benzoates, chlorobutanol, polyethylene glycols, vegetableoils, olive oil, castor oil, mineral oil, fumarates, malates, oxalates,succinates, butyrates, cetyl alcohol esters, malonates, polysorbates,glycerine, N-butylbenzenesulfonamide, N-methylpyrrolidone, and mixturesthereof.
 15. The method of claim 7, wherein the plasticizer comprisesdiethyl phthalate.
 16. The method of claim 7, wherein the ER coatingcomposition comprises ethylcellulose and diethyl phthalate dissolved ina solvent comprising acetone and water at a acetone/water weight ratioranging from about 85/15 to about 98/2.
 17. The method of claim 7,wherein the ratio of water-insoluble polymer to plasticizer is about9:1.
 18. The method of claim 1, wherein the drug layering compositioncomprises cyclobenzaprine hydrochloride, and after drying, the druglayered beads comprise from about 20 wt. % to about 30 wt. %cyclobenzaprine hydrochloride.
 19. The method of claim 18, wherein thedrug layering composition comprises cyclobenzaprine hydrochloride, andafter drying, the drug layered beads comprise about wt. %cyclobenzaprine hydrochloride.
 20. The method of claim 1, wherein the IRbeads comprise about 2% of the pharmaceutically acceptable water solublepolymer.
 21. The method of claim 1, wherein the ER beads comprise about7% to about 12% of the pharmaceutically acceptable water insolublepolymer.
 22. The method of claim 7, wherein the ER beads comprise about9% of the pharmaceutically acceptable water-insoluble polymer andplasticizer.
 23. The method of claim 1, wherein the ER beads provide adrug release profile that does not deviate by more than about 10% at anytime point in the following dissolution pattern: after 2 hours, no morethan about 40% of the total active is released; after 4 hours, fromabout 40-65% of the total active is released; after 8 hours, from about60-85% of the total active is released; and optionally after 12 hours,from about 75-85% of the total active is released, when tested usingUnited States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm) in 900 mL of0.1 N HCl at 37° C.
 24. The method of claim 1, wherein the ER beadsprovide a drug release of about 20% to about 50% after 2 hours whentested using United States Pharmacopoeia Apparatus 2 (paddles @ 50 rpm)in 900 mL of 0.1 N HCl at 37° C.
 25. The method of claim 1, wherein saidcoating step b) is carried out under an atmosphere having a dew pointranging from about 6-17° C.
 26. The method of claim 2, wherein saidcuring step c) is carried out under an atmosphere having a dew pointranging from about 6-17° C.
 27. The method of claim 1, wherein saidcoating step a) is carried out under an atmosphere having a dew pointranging from about 6-17° C.
 28. The method of claim 1, wherein thepharmaceutical composition comprises 30 mg of cyclobenzaprine HCl andprovides a maximum blood plasma concentration (C_(max)) within the rangeof about 80% to 125% of about 19.9 ng/mL of cyclobenzaprine HCl and anAUC₀₋₁₆₈ within the range of about 80% to 125% of about 736.6 ng·hr/mLfollowing a single oral administration thereof.
 29. The method of claim1, wherein the pharmaceutical composition comprises 15 mg ofcyclobenzaprine HCl and provides a maximum blood plasma concentration(C_(max)) within the range of about 80% to 125% of about 8.3 ng/mL ofcyclobenzaprine HCl and an AUC₀₋₁₆₈ within the range of about 80% to125% of about 318.3 ng·hr/mL following a single oral administrationthereof.